2 - phenyl - 3 - (1 - azaspiro(4.5)dec - 1 - yl and 1-azaspiro(4.4)non-1-yl)-propiophenones



United States Patent U.S. Cl. 260326.5 3 Claims ABSTRACT OF THE DISCLOSURE This invention relates to novel 2-phenyl-3-(1-azaspiro [4.5]dec-l-yl)-propiophenones and their 1-azaspiro[4.4] non-l-yl counterparts; it is inclusive of the free base and acid addition salt forms of the compounds embraced by the formula wherein n is selected from the group consisting of one and two, R and R" are selected from the group consisting of hydrogen and lower-alkyl, and X and X are selected from the group consisting of hydrogen, lower-alkyl, fluorine, chlorine and bromine.

As used in this specification, the term lower-alkyl means alkyl of from one through four carbon atoms, e.g., methyl, ethyl, propyl, butyl, and isomeric forms thereof.

CROSS REFERENCE TO RELATED APPLICATIONS Ser. No. 747,450'filed of even date covering novel 2- phenyl 3 (3 azabicyclo[3.2.2]nonan 3 yl) propiophenones and 2-pheny1-3-(2-azabicyclo [2.2.2] octan-2-yl) propiophenones.

Ser. No. 747,428 filed of even date covering novel 2- phenyl-3-tertiaryamino-1-(2-thienyl)-1-propanones.

Ser. No. 747,426 filed of even date covering 2-phenyl- 3- 3 -quinuclidinylamino -propiophenones.

Ser. No. 747,425 filed of even date covering 2-phenyl- 3-(4-hydroxy-4-phenylpiperidino)-propiophenones.

Ser. No. 747,483 filed of even date covering 2-phenyl- 3-(3-pyrrolin-1-yl)-propiophenones.

BRIEF SUMMARY OF THE INVENTION The novel compounds embraced by Formula I exist either in the non-protonated (free base) form or in the protonated (acid addition salt) form, depending on the pH of the environment. They form stable protonates, i.e., acid addition salts, on neutralization of the free base with suitable acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, benzoic salicylic, glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic, methanesulfonic, cyclohexanesulfamic, picric and lactic acids, and the like.

0 I C=CH2 Cr fil wherein X and X have the same meaning as above, with an approprlate secondary amine of the formula RI! RI III wherein n, R and R" have the significance defined above.

2-phenylacrylophenones (II) are known in the art, and can be prepared in the manner described in Bull. Soc. Chim. France 1176 (1963).

The secondary amines of Formula III are known in the art and can be prepared by published methods; e.g., in accordance with the procedures described in J. Amer. Chem. Soc. 79, 3186 (1957) and U.S. Pats. 2,812,334; 2,814,622; 2,911,409; 2,971,961.

In carrying out the reaction between the acrylophenones (II) and the azaspiro compounds (IH), the two reactants are merely mixed. Inert solvents can be employed, if desired. Heating of the reaction mixture is not necessary. The molecular ratio of the compounds of Formula II and Formula III can be varied, substantially equimolar ratios having been found satisfactory. The time required for the completion of the reaction depends upon such factors as the particular reactants, their solubility, their relative amounts, thoroughness of mixing, and the like. There- 'fore, it will be understood that the optimum reaction time will vary for each set of reaction conditions. Ordinarily, reaction times ranging from about several hours to about ten days are suitable. After completion of the reaction between the compounds of Formula II and Formula III, the product (I) is isolated from the reaction mixture in its free base form, using conventional procedures such as filtration, solvent evaporation, solvent extraction, chromatography or crystallization, or a combination of these methods. The free bases so obtained can be purified, e.g., by recrystallization from a solvent or suitable mixture of solvents. The free base form can be converted to any acid addition salt by neutralization with an acid, e.g., any of those given above.

The compounds of Formula I have pharmacological activity. They depress the central nervous system; consequently, they can be used as sedatives and tranquilizers in mammals and animals, e.g., mice, rats and birds. They also antagonize convulsions and prevent death resulting from the administration of nicotine to mice.

DETAILED DESCRIPTION It is to be understood that the invention is not to be limited to the exact details of operation or exact compositions shown and described herein, as obvious modifications and equivalents will be apparent to those skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

PREPARATION 1 2-phenylacrylophenone or 1,2-diphenyl-2-pr0penl-one) (II A solution of 294 g. (1.5 moles) of phenyl benzyl ketone (also known as desoxvbenzoin), 360 ml. of 37% formaldehyde, and 7.5 m1. of piperidine in 1.35 l. of methanol in a 5 l. flask is stirred under reflux for about 3 hours and allowed to stand for about 16 hours. The mixture is diluted with 2 l. of water and the resulting oil extracted with 2 l. of ether in 2 portions. The ether solutions are washed successively with 150 ml. of aqueous 5% hydrochloric acid solution, 200 ml. of 5% aqueous sodium bicarbonate solution, 300 ml. of water, saturated aqueous sodium chloride solution, and dried over sodium sulfate. After filtration, the solvent is evaporated and the resulting syrup distilled from a Claisen flask to give 266.6 g. (85% yield) of 2-phenylacrylophenone (II) as a colorless oil having a boiling point of 205 to 207 C. (at 15 mm. of Hg). This material crystallizes and is stable at C.

Following the procedure of Preparation 1, but substituting for phenyl benzyl ketone the following:

(1) Phenyl p-chlorobenzyl ketone,

(2) p-Bromophenyl p-bromobenzyl ketone, (3) m-Chlorophenyl m-chlorobenzyl ketone, (4) p-Fluorophenyl benzyl ketone,

(5) p-Chlorophenyl p-methylbenzyl ketone, (6) o-Propylphenyl o-bromobenzyl ketone, (7) o-Bromophenyl m-ethylbenzyl ketone,

(8) m-Fluorophenyl p-butylbenzyl ketone,

(9) p-Methylphenyl p-methylbenzyl ketone, (10) o-Butylphenyl p-butylbenzyl ketone, etc.,

there can be prepared, respectively,

( 1) 2-(p-chlorophenyl)-acrylophenone (II) (2) 2-(p-bromophenyl)-4'-bromoacrylophenone (II,

( 3) 2-(m-chlorophenyl)-3'-chloroacrylophenone (II), (4) 2-phenyl-4-fluoroacrylophenone (II),

(5) 2-(p-methylphenyl)-4'-chloroacrylophenone (II), (6) 2-(o-bromophenyl)-2'-propylacrylophenone (II), (7) 2-(m-ethylphenyl)-2'-bromoacrylophenone (II), (8) 2- (p-butylphenyl)-3'-fluoroacrylophenone (II),

(9) 2-(p-methylphenyl)-4'-methylacrylophenone (II), (10) Z-(p-butylphenyl) -2-butylacrylophenone (II), etc.

EXAMPLE 1 Z-pheny l-3- I -azaspiro [4 .5 dec-I -yl propiophenone (I) A mixture of 31.2 g. (0.15 mole) of distilled 2-phenylacrylophenone (II) in 20.75 g. (0.15 mole) of l-azaspiro- [4.5]decane (III) crystallizes after standing for about 6 days. The solid is recrystallized from 165 ml. of 2- propanol, by filtering while hot and cooling, to give 40 g. of white crystalline 2-phenyl-3-(l-azaspiro[4.5]dec-1- yl)-propiophenone (I), melting between 71 and 72.5 C.

Analysis.Calcd. for C H NO (percent): C, 82.95; H, 8.41; N, 4.03. Found (percent): C, 82.85; H, 8.63; N, 3.97.

Infrared and nuclear magnetic resonance (NMR) spectra support the proposed structure of the thus produced compound.

Following the procedure of Example 1, but substituting for 2-phenylacrylophenone (II) the following:

(1) 2-(p-chlorophenyl) acrylophenone (II),

(2) 2-(p-bromophenyl)-4'-bromoacrylophenone (H), (3) 2-(m-chlorophenyl)-3'-chlor0acrylophenone (II), (4) 2-phenyl-4'-fluoroacrylophenone (II),

(5) Z-(p-methylphenyl)-4'-chloroacrylophenone (II),

4 (6) 2-(o-bromophenyl)-2'-propylacrylophenone (II) (7) Z-(m-ethylphenyl)-2-bromoacrylophenone (II), (8) 2-(p-buty1phenyl)-3'-fiuoroacrylophenone (II), (9) 2-(p-methylphenyl)-4'-methylacrylophenone (II), (10) 2-(p-butylphenyl)-2'-butylacrylophenone (II), etc.

there can be prepared, respectively,

(1) 2- (p-chlorophenyl) -3 l-azaspiro [4.5]dec-1-yl) propiophenone (I) 2) 2-(p-bromophenyl)-3-( l-azaspiro[4.5]dec-1-yl)- 4'-bromopropiophenone (I) (3 2- (m-chlorophenyl) -3-( l-azaspiro [4.5 decl-yl 3 '-chloropropiophenone (I) 4) 2-phenyl-3- l-azaspiro [4.5] dec-1-yl)-4'- fluoropropiophenone (I),

( 5) 2-(p-methylphenyl)-3-(1-azaspiro[4.5]dec-1-yl)- 4'-chloropropiophenone (I) (6) 2-(o-bromophenyl)-3- 1-azaspiro[4.5] dec-1-yl)- 2'-propylpropiophenone (I),

( 7) 2-(m-ethylphenyl)-3-( l-azaspiro[4.5]-1-yl) -2'- bromopropiophenone (I) (8 2- (p-butylphenyl-3- l-azaspiro 4.5 decl-yl) 3 '-fluoropropiophenone (I),

(9) 2-(p-methylphenyl)-3-(l -azaspiro [4.5 dec-l-yl) 4'-methylpropiophenone (I) 10) 2- (p-butylphenyl -3 l-azaspiro [4.5]dec-1-yl) 2'-butylpropiophenone (1), etc.

Following the procedure of Example 1, but substituting for l-azaspiro [4.5]decane (III) the following:

(1) 2-methyl-1-azaspiro [4.5]decane (III),

(2) 2-ethyl-1-azaspiro[4.5]decane (III),

(3) 2-propyl-3-ethyl-1-azaspiro[4.5]decane (III), (4) 2,3-dimethyl-1-azaspiro [4.5]decane (III),

(5 2,3-dibutyl-1-azaspiro[4.5]decane (III), etc.,

there can be prepared, respectively,

(1) 2-phenyl-3-(2-methyl-1-azaspiro[4.5]dec-lyl)-pr0piophenone (I),

(2) 2-phenyl-3- 3-ethyll-azaspiro [4.5 dec-lyl)-propiophenone (I),

(3) 2-phenyl-3-(2-propyl-3ethyl-l-azaspiro[4.5]dec-1- yl)-propiophenone (I),

(4) 2-phenyl-3-(2,3-dimethyl-l-azaspiro[4.5]decy-1- yl)-propiophenone (I),

(5) 2-phenyl-3-(2,3-dibutyl-1-azaspiro[4.5] dec-lyl)-propiophenone (I), etc.

Following the procedure of Example 1, but substituting for 2-phenylacrylophenone (II) and l-azaspiro [4.5]decane (III) the following:

( 1) 2-(p-chlorophenyl)acrylophenone (II) and 2- methyl-1-azaspiro[4.5] decane (HI) (2) 2-(p-bromophenyl)-4'-bromoacrylophenone (II) and 2-ethyl-1-azaspiro [4.5] decane (HI),

(3) 2-(m-chlorophenyl)-3'-chloracrylophenone (II) and 2-pr0pyl-3 -ethyl-1-azaspiro [4.5]decane (III),

(4) 2-phenyl-4'-flu0roacrylophenone (II) and 2,3-dimethyl-1-azaspiro[4.5]decane (III),

(5) Z-(p-methylphenyl)-4'-chloroacrylophenone (II) and 2,3-dibutyl-l-azaspiro[4.5]decane (III),

(6) 2-(o-bromophenyl)-2-propylacrylophenone (II) and 3-methyl-1-azaspiro[4.5]decane (III),

(7) 2-(m-ethylphenyl)-2'-bromoacrylophenone (II) and 2-ethyl-1-azaspiro [4.5] decane (HI).

(8) 2-(p-butylphenyl)-3'-fluoroacrylophenone (II) and 2- ethyl-3-propyll-azaspiro [4.5 ]decane (III),

(9) 2-(p-methylphenyl)-4-methylacrylophenone (II) and 2,3-diethyl-1-azaspiro [4.5] decane (III),

(10) 2-(p-butylphenyl)-2'-buty1acrylophenone (II) and 2,3-dibuty1-1-azaspiro[4.5]decane (III), etc.,

there can be prepared, respectively,

(1) Z-(p-chlorophenyl)-3-(2-methyl 1 azaspiro[4.5]-

dec-1-yl)-propi0phenone (I),

(2) 2-(p-bromophenyl)-3-(2-ethyl 1 azaspiro[4.5]decl-yl)-4-bromopropiophenone (I), (3) 2-(m-chlorophenyl)-3-(2-propyl-3-ethyl 1 azaspiro- [4.5]dec-l-yl)-3'-chloropropiophenone (I), (4) -2-phenyl-3-(2,3-dimethyl 1 azaspiro[4.5]dec-1-yl)- 4'-fluoropiophenone (I), (5) 2-(p-methylphenyl)-3-(2,3-dibutyl 1 azaspiro- [4.5]dec-l-yl)-4'-chloropropiophenone (I), (6) 2-(o-bromophenyl)-3-(3-methyl 1 azaspiro[4.5]-

l-yl)-2-propylpropiophenone (I) (7) 2-(m-ethylphenyl)-3-(2-ethyl 1 azaspiro[4.5]decl-yl)-2'-bromopropiophenone (I), Y (8) 2-(p-butylphenyl)-3-(2-ethyl 3 propyl-l-azaspiro- [4.5]deo-l-yl)-3-fiuoropropiophenone (I), (9) Z-(p-methylphenyl) -3-(2,3-diethyl 1 azaspiro[4.5]-

dec-l-yl)-4'-methylpropiophenone (I), (10) 2-(pbutylphenyl)-3-(2,3-dibutyl 1 azaspiro[4.5]-

dec-l-yl)-2-butylpropiophenone (1), etc.

EXAMPLE 2 2-phenyl-3-(1-azaspir0[4.5]dec-1-yl)- propiophenone hydrochloride (I) A solution of 39.1 g. (0.113 mole) of the free base form of 2-phenyl-3-(1-azaspiro [4.5]dec 1 y1)-propiophenone (I) obtained in Example 1 in 400 ml. of 2-propanol is chloride (I) as white crystals melting between 167 and 168.5 C. The filtrate from the crystallization of the free base (Example 1) is acidified with ethanolic hydrogen chloride to yield an additional 5 g. of 2-phenyl-3-(1-azaspiro [4.5]dec 1 yl)-propiophenone hydrochloride (I) melting between 169 and 170 C. The overall yield is 81% of the theoretical.

Analysis-Calcd. for C H ClNO (percent): C, 75.07; H, 7.88; Cl, 9.24; N, 3.65. Found (percent): C, 75.20; H, 8.07; Cl,.9.46; N, 3.28.

On neutralization of the thus obtained hydrochloride (1) with sodium or potassium hydroxide, the free base form, 2-phenyl 3 (1-azaspiro[4.5]dec-1-yl)-propiophenone (I) is produced.

Following the procedure of Example 2, but substituting for hydrogen chloride acid another acid, e.g., hydrobromic, sulfuric, phosphoric, acetic, benzoic, salicylic, citric, succinic, malic, cyclohexanesulfamic, etc., the corresponding acid addition salt of 2-phenyl-3-(1-azaspiro[4.5]dec-lyl)-propiophenone (I) can be prepared.

Following the procedures of the immediately preceding paragraph and of Example 2, but substituting for the free base form of 2-phenyl-3-(1-azaspiro[4.5]dec-1-yl)propiophenone (1) other compounds embraced by Formula I, such as those designated (1) htrough (10) in the paragraph directly above Example 2, their corresponding acid addition salts can be prepared.

EXAMPLE 3 2-phenyl-3-(1 -azaspiro [4 .4 non-1 -yl propiophenone (1) Following the procedure of Example 1, and employing Z-phenylacrylophenone (II) as one of the reactants but substituting l-azaspiro[4.5]nonane (HI) for l-azaspiro- [4.5]decane (HI), 2-phenyl 3 (1-azaspiro[4.4]non-1- yl)-propiophenone (I) can be prepared.

Following the procedure of Example 3, but substituting for Z-phenylacrylophenone (II) the following:

(1) Z-(p-chlorophenyl)acrylophenone II).

(2) 2-(p-bromophenyl)-4'-bromoacrylophenone (II), (3) 2-(m-chlorophenyl)-3-chloroacrylophenone (II), (4) 2-phenyl-4'-fluoroacrylophenone (H),

(5) Z-(p-methylphenyl)-4'-chloroacrylophenone (II), (6) 2-(o-bromophenyl)-2'-propylacrylophenone (II), (7) Z-(m-ethylphenyl)-2'-bromoacry1ophenone (II),

(8) 2-(p-butylphenyl)-3'-fluoroacrylophenone II),

6 (9 2- (p -methylphenyl) -4'-methylacrylophenone (II),

, (l0) 2-(p-butylphenyl)-2-butylacrylophenone (II), etc.,

there can be prepared, respectively,

Following the procedure of Example 3, but substituting for 1-azaspiro[4.4]nonane (III) the following:

( 1) 2-methyll-azaspiro [4.4] nonane (HI),

(2) 3-ethyl-1-azaspiro[4.4]nonane (III),

(3) 2-propyl-3-ethyl-l-azaspiro[4.4]nonane (III), (4) 2,3-dimethyl-1-azaspiro[4.4]nonane (III), (5) 2,3-dibutyl-1-azaspiro[4.4]nonane (III), etc.,

there can be prepared, respectively,

(1 2-phenyl-3- (2-methyl-l-azaspiro [4.4]non-1-yl)- propiophenone (I),

(2) 2-phenyl-3-(3-ethyl-l-azaspiro [4.4]non-1-yl) propiophenone (I),

(3 2-phenyl-3-(2-propyl-3-ethyl-1-azaspiro [4.4]n0n-1- yl)-propiophenone (I),

(4) 2-phenyl-3-(2,3-dimethyl-1-azaspiro[4.4]non-l-yl)- propiophenone (I),

(5 2-phenyl-3-(2,3-dibutyl-1-azaspiro[4.4]non-1-yl) propiophenone (I), etc.

Following the procedure of Example 3, but substituting for Z-phenylacrylophenone (II) and l-azaspiro[4.4] nonane (III) the following:

(1) 2-(p-chlorophenyl)acrylophenone (II) and Z-methyll-azaspiro[4.4]nonane (III),

(2) 2-(p-bromophenyl)-4'-bromoacrylophenone (II) and 2-ethyl-l-azaspiro[4.4] nonane (III),

(3) 2- (m-chlorophenyl)-3-chloroacrylophenone (II) and 2-propyl-3-ethyl-1-azaspiro[4.4] nonane (III),

(4) 2-phenyl-4'-fluoroacrylophenone (l1) and 2,3-

dimethyl-l-azaspiro[4.4]nonane (III),

(5) 2-(p-methylphenyl)-4'-chloroacrylophenone (II) and 2,3-dibutyl-1-azaspiro [4.4]nonane (HI),

(6) 2-(o-bromophenyl)-2-propylacrylophenone (II) and 3-methyl-1-azaspiro[4.4] nonane ('III) (7) 2-(m-ethylphenyl)-2'-bromoacrylophenone (II) and 2-ethyl-1-azaspiro [4.4] nonane (III) (8) 2-(p-butylphenyl)-3'-fluoroacrylophenone (H) and 2-ethyl-3-propyl-l-azaspiro[4.4]nonane (HI),

(9) 2-(p-methylphenyl)-4'-methylacrylophenone (H) and 2,3-diethyl-1-azaspiro-[4.4]nonane (IH),

(10) 2-(p-butylphenyl)-2-butylacrylophenone (H) and 2,3-dibutyl-1-azaspiro[4.4]nonane (IH), etc.,

there can be prepared, respectively,

( 1 2- (p-chlorophenyl) -3-(2-methyl-1-azaspiro[4.4]non- 1-yl)-propiophenone (I),

(2) 2-(p-bromophenyl)-3-(3-ethyl-1-azaspiro[4.4]nonl-yl)-4'-bromopropiophenone (I),

7 (3) 2- (m-chlorophenyl)-3-(2-propyl-3-ethyl-1- azaspiro[4.4]non-1-yl) -3 -chloropropiophenone (-I) (4) 2-phenyl-3-(2,3-dimethyl-1-azaspiro [4.4] non-1-yl)- 4'-fiuoropropiophenone (I), (5 2-(p-methylphenyl)-3-(2,3-dibutyl-1- azaspiro [4.4]non-1-yl) -4'-chloropropiophenone (I), (6) 2-(p-bromophenyl)-3-(3-methyl-1-azaspiro[4.41non- 1-yl) -2'-propylpropiophenone (I) (7) Z-(m-ethylphenyl) -3-(2-ethyl-1-azaspiro [4.4]non-1- yl)-2'-bromopropiophenone (I), (8) 2- (p-butylphenyl)-3- (2-ethyl-3-pr0pyl-1- azaspiro [4.4]n0n-1-yl) -3 '-fluoropropiophenone (I), (9) 2-(p-methylphenyl)-3-(2,3-diethyl-1- azaspiro[4.4] nonl-yl) -4-methylpr0pi0phenone (I) (10) 2- (p-butylphenyl) -3- (2,3-dibutyl-1- azaspiro [4.4] nonl-yl) -2-butylpropiophenone (I), etc.

EXAMPLE 4 2-phenyl-3- (1 -azaspir0[4.4] now-1 -yl -pr0pi0phen0nehydrochloride (I) Following the procedure of Example 2, but substituting 2 phenyl-3-(l-azaspiro [4.4] n0n-1-yl)-propiophenone (I) for 2 phenyl-3-( l-azaspiro[4.5]dec-1-yl)-propiophenone (I) (and employing ethanolic hydrogen chloride in the manner of Example 2) 2-phenyl-3-(l-azaspiro[4.4] non-1- yl)-propiophenone hydrochloride (I) can be prepared.

On neutralization of the thus obtained hydrochloride (I) with sodium hydroxide or potassium hydroxide, the free base form, 2 phenyl-3-(1-azaspiro[4.4] nonan-1-yl)-propionphenone( I) is produced.

Following the procedure of Example 4, but substituting for hydrogen chloride acid another acid, e.g., hydrobromic, sulfuric, phosphoric, acetic, benzoic, salicylic, citric, succinic, malic, cyclohexanesulfamic, etc., the corresponding acid addition salt of 2-phenyl-3-(1-azaspir0- [4.4]non-1-y1)propiophenone (I) can be prepared.

Following the procedures of the immediately preceding paragraph and of Example 4, but substituting for the free base form of 2-phenyl-3-(1-azaspiro[4.4] non-l-yl)-propiophenone (I) other compounds embraced by Formula O JCHCH2N wherein n is selected from the group consisting of one and two, R and R" are selected from the group consisting of hydrogen and lower-alkyl, and X and X are selected from the group consisting of hydrogen, lower-alkyl, fluorine, chlorine and bromine, and (2) an acid addition salt thereof.

2. A compound of claim 1 wherein n is two and R, R, X and X are hydrogen, namely, 2-phenyl-3-(1-azaspiro [4.5 decl-yl) -propiophenone.

3. An acid addition salt of a compound of claim 1 wherein n is two, R', R", X and X are hydrogen, and the acid addition salt is that of hydrogen chloride, namely, 2- pheny1-3- l-azaspiro[4.5]dec-1-y1)-propiophenone hydrochloride.

References Cited UNITED STATES PATENTS 3,203,962 8/1965 Huebner.

ALEX MAZEL, Primary Examiner J. A. NAPCAVAGE, Assistant Examiner US. Cl. X.R. 

